Articular chondrocytes mount a pleiotropic response to interleukin-1 (IL- 1), which includes the increased synthesis of prostaglandins and matrix metalloproteinases, but a decreased synthesis of matrix macromolecules. Fragments of articular cartilage undergo an autolytic response to IL-1, in which proteoglycans are released from the matrix; the precise mechanisms of matrix breakdown remain unclear. The depolymerization of hyaluronan is particularly mysterious, as no extracellular, neutral hyaluronidase is found in the joint. We have recently made the novel observation that articular chondrocytes synthesize very large quantities of the free radical nitric oxide (.NO) following treatment with IL-1. In attempting to identify a role for . NO in cartilage metabolism, we have noted that .NO degrades hyaluronan in vitro. This invites the hypothesis that the breakdown of hyaluronan by chondrocyte-derived .NO accounts for at least some of the loss of proteoglycans from IL-1 treated cartilage. The present application addresses this hypothesis; we propose to do so at three levels. First, the chemical breakdown of hyaluronan by .NO will be investigated by viscometry and size-exclusion chromatography. Second, the ability of cell cultures of articular chondrocytes to degrade hyaluronan in an .NO- dependent manner will be studied. Third, the ability of organ cultures of articular cartilage to degrade their own endogenous hyaluronan, and to release proteoglycans from their matrix, in .NO-dependent manner will be studied. Should the results of these investigations support a role for .NO in cartilage catabolism, they will identify a novel target for therapeutic intervention in the arthritic joint.